Targeting death receptors (DRs) for cancer therapy holds promise due to their ability to trigger apoptosis in malignant cells. However, the broad expression of DRs in both cancerous and normal tissues has hindered clinical success, primarily due to systemic toxicity. To overcome this limitation, we engineered a DNA origami-based nanorobot that performs conditional, tumor-specific activation of DRs through autonomous structural switching in response to the acidic tumor microenvironment. The nanodevice is constructed with a programmable triplex DNA lock that remains stable at physiological pH (7.4), keeping six TRAIL-mimicking peptide ligands concealed within a closed nanocavity. Under acidic conditions (pH ~6.5), characteristic of solid tumors, the triplex lock dissociates, inducing an open conformation that presents the ligands in a precise 10-nm hexagonal pattern—an arrangement previously shown to be optimal for DR clustering and activation.

We demonstrate that this pH-triggered conformational change results in a potent induction of apoptosis in breast cancer cells in vitro. In vivo, intratumoral administration of the nanorobot in a xenograft mouse model significantly reduced tumor burden—achieving up to 70% tumor growth inhibition—while sparing healthy tissue and avoiding off-target effects. This system exemplifies a new class of “smart” nanomedicines that integrate environmental sensing with spatially organized ligand presentation to execute therapeutic functions with high precision. Our work provides a proof of concept for logic-gated, stimuli-responsive DNA nanorobots with potential applications in targeted cancer therapy and precision medicine.